1. Field of the Invention
The present invention relates to new polynucleotides derived from the nucleotide sequence of the IFNα-21 gene comprising new SNPs, and new polypeptides derived from the natural wild-type IFNα-21 protein comprising mutations caused by these SNPs, as well as their therapeutic uses.
2. Related Art
The interferon alpha 21 gene, hereinafter referred to as IFNα-21, is described in the publications:
Goeddel, D. V., Leung, D. W; “The structure of eight distinct cloned human leukocyte interferon cDNAs”; Nature 290 (5801), 20-26 (1981).
Olopade O I., Bohlander S K.; “Mapping of the shortest region of overlap of deletions of the short arm of chromosome 9 associated with human neoplasia”; Genomics 14 (2), 437-443 (1992).
The nucleotide sequence of this gene is accessible in the HTG section of the GenBank database under accession number AC009445.
The sequence of the messenger RNA of IFNα-21 is mentioned in the database of the NCBI, under accession code NM—002175.
IFNα-21 is a gene possessing a structural and functional homology close to that of human interferons alpha (IFNα), specifically IFNα-2.
The IFNα are known for their cellular antiproliferative effects and their involvements in antiviral and antiparasitic responses.
The IFNα are also known to inhibit the expression of several other cytokines at the level of the hematopoietic stem cells, as well as to inhibit the cellular proliferation of certain tumors.
The IFNα are known for their cellular antiproliferative effects and their involvements in antiviral and antiparasitic responses.
The IFNα are also known to inhibit the expression of several other cytokines at the level of the hematopoietic stem cells, as well as to inhibit the cellular proliferation of certain tumors.
The IFNα are also known to reduce the expression of the receptors to the EGF in renal carcinomas, to inhibit the expression of certain mitochondrial genes, to inhibit the proliferation of fibroblasts, monocytes and B lymphocytes, especially in vitro, and to block the synthesis of antibodies by B lymphocytes.
The IFNα are also known to induce the expression of tumor specific antigens on the surface of tumor cells and also to induce the genes placed under the control of promoter regions of the ISRE type (Interferon-Stimulated Response Element) by acting on the specific transcription factors of these ISRE.
It is known that the IFNα are involved in different disorders and/or human diseases, such as the different cancers like for example, carcinomas, melanomas, lymphomas, leukemias and cancers of the liver, neck, head and kidneys, cardiovascular diseases, metabolic diseases such as those that are not connected with the immune system like, for example, obesity, infectious diseases such as hepatitis B and C and AIDS, pneumonias, ulcerative colitis, diseases of the central nervous system like, for example, Alzheimer's disease, schizophrenia and depression, the rejection of tissue or organ grafts, healing of wounds, anemia in dialyzed patients, allergies, asthma, multiple sclerosis, osteoporosis, psoriasis, rheumatoid arthritis, Crohn's disease, autoimmune diseases and disorders, gastrointestinal disorders or even disorders connected with chemotherapy treatments.
The IFNα are particularly used for the treatment of certain leukemias, metastasized renal carcinomas as well as tumors that appear following an immunodeficiency, such as Kaposi's sarcoma in the case of AIDS. The IFNα are also effective against other types of tumors and against certain viral infections. The IFNα are also recognized by the FDA (Food and Drug Administration) for the treatment of genital warts or venereal diseases.
More specifically, IFNα-21 was located by in situ hybridization in the brains of patients suffering from Parkinson's disease or Alzheimer's disease.
Compared to other cells, microglial cells express IFNα-21 in large quantities.
In patients suffering from Alzheimer's disease, the presence of IFNα-21 was shown in the neurons of the parietal lobes, suggesting that IFNα-21 may be involved in this pathology (See e.g., Kawaguchi N, Yamada T, Yoshiyama Y. No To Shinkei. 1997 January; 49(1): 69-73).
However, the IFNα, and in particular IFNα-21, have numerous side effects when they are used in pharmaceutical compositions, such as reactions of acute hypersensitivity (urticaria, bronchoconstriction, anaphylactic shock etc.), cardiac arrythmias, low blood pressure, epileptic seizures, problems with thyroid functions, flu-like syndromes (fevers, sweats, myalgias), etc.
Furthermore, the patients treated with IFNα can develop antibodies neutralizing these molecules, thus decreasing their effectiveness.
The inventors have found new polypeptide and new polynucleotide analogs to the IFNα-21 gene capable of having a different functionality from the natural wild-type IFNα-21 protein.
These new polypeptides and polynucleotides can notably be used to treat or prevent the disorders or diseases previously mentioned and avoid all or part of the disadvantages, which are tied to them.